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Sell first, test later?

The more I look at the world of phototherapeutic devices, the more I come to the conclusion that selling the device seems to be more important than establishing properly whether it works or not.

I’m not saying that people selling devices don’t do any testing – just that some of them seem too satisfied with preliminary studies. They do a small study, get a positive result and claim that their product is ‘medically’ or ‘clinically proven’.

If you think that I’m being harsh, then have a look at a recent Daily Mail article, “Could LED light the way in the treating of Alzheimer’s?” It starts off discussing the serious topic raised in the headline and goes on to provide five excellent examples of therapeutic devices being promoted using evidence which is preliminary at best and non-existent at worst.

First, it would be marvellous if there was an effective way of treating Alzheimer’s. If this turned out to be irradiating people’s heads with infrared, fantastic! So, what is the answer to the question posed by the headline? The current answer is: no one knows. That is why as the article pointed out, research is ongoing. It may even be that the answer is: unlikely. Several experts have cast doubt over the basic plausibility of this approach.

Again, it would be great if these worked; as we shall see the claims made for the products are ahead of the evidence.

In the early part of the article the Mail claims that, “The light in LED clock displays and other electronic gadgets could heal broken skin, help hair regrow and may even offer hope to sufferers of Alzheimer’s disease.”

How does it justify this optimism? It quotes some respectable scientists, who mainly focus on in vitro effects,

“[infrared radiation] is thought to stimulate the growth of cells of all types of tissue”

This is a reasonable statement from a researcher, “who is assessing whether infrared light could reverse the symptoms of Alzheimer’s”.

I’ve commented on press statements describing this research previously. Some experts are not at all optimistic; perhaps that’s due to the radiation this device uses being only very weakly absorbed by tissue. This is both a necessity and a problem: if a wavelength which would be more strongly absorbed by brain cells were used, it would be strongly attenuated by the structures of the head – not getting where it was needed. Choosing a wavelength that will penetrate to the brain, as this device does, seems to limit the dose of infrared radiation delivered to the brain and hence any putative therapeutic effect.

Even though this technique is very much a work in progress, the Mail have covered its use on a couple of individuals, a US company director called Clem Fennel and the well-known author Sir Terry Pratchett. Mr Fennel was said to have made, “an astonishing recovery in just three weeks.” On the other hand, the Mail say that Sir Terry Pratchett saw a, “small, but measurable, improvement in his condition after three months.” All these anecdotes demonstrate is that a proper trial is needed. (This has been covered in detail by Martin, over at The Lay Scientist blog. David Gorski also made some interesting observations on the original media story on the Science-Based Medicine blog)

The next scientist quoted by the Mail again talks about the effect on cells rather than people,

“Cells have been found to grow 150 per cent to 200 per cent faster than cells not given an infrared bath”

He has, reportedly, conducted trials where throat and mouth ulcers in cancer patients were prevented and treated by using, “infrared light for 80 seconds a day for two weeks. ” (This paper perhaps?)

He also provides a very optimistic quote for the Mail; let’s hope that it comes to pass,

“LED infrared light might one day help those who are paralysed to walk again. It could also prevent certain forms of blindness. There are all sorts of potential uses.”

Other academic authority is invoked by noting that, “the University of Tel Aviv, infrared light promoted healing in people with nasal allergies.”

This sounds very much like the oft quoted paper by Neuman and Finkelstein (1997). This looked at (visible) red light phototherapy for the treatment of perennial allergic rhinitis. It’s a small study, which doesn’t report the drop out rate. It also assessed eleven different outcomes, delivering a 43% probability of a chance positive finding.

Worse still, the sham treatment was no illumination – making it blindingly obvious who was getting treatment and who wasn’t. This Rudolph Effect is likely to boost expectancy effects in the treated group: my nose is glowing red; it must be doing me some good! A small trial that’s effectively unblinded is not much use.

Claims are also made by the authors concerning the mechanism of action, but no data is provided to support their speculation. Over a decade later, the work has not been replicated and reported in any PubMed listed journal.

The paucity of evidence doesn’t seem to have held back commercial exploitation. A variant of the device investigated by Neuman and Finkelstein is included in the articles’, “Five of the best infrared healing products”.

“Nasal allergies

Placing two probes that emit infrared light into the nostrils could eliminate allergic symptoms.

I guess that it could,”eliminate allergic symptoms”. Lots of unlikely things could happen. At just shy of eighty pounds, it’s also rather expensive. The LloydsPharmacy version is a lot cheaper – though maybe the price tag just might deliver an extra boost to the placebo effect!

My take on this: If it really worked, then why have no follow-up studies been reported? This study is, perhaps, good enough to justify more rigorous trials. It isn’t enough to justify selling a therapeutic device.

“Muscle pain and stiff joints

Infrared light has been shown to promote muscle relaxation and boost blood flow. If you have stiff joints or muscular pain, try using the Infrared Bodyzone Muscle Treatment Lamp.

Try as I might I can’t find anything that looks like a trial of this device listed in PubMed (If anyone can find it I’d love to see it). As it stands, it does make me wonder why, if the work was really independent and positive, it hasn’t been published in a reputable journal.

Now it is true that the use of heat lamps for aches and pains is a very long standing practise. I remember my grandparents having one. So the paucity of published evidence did surprise me.

“There is moderate evidence that heat wrap therapy reduces pain and disability for patients with back pain that lasts for less than three months. The relief has only been shown to occur for a short time and the effect is relatively small. […]

In fact, this is indirect evidence as none of the included studies used heat lamps. However it speaks to a basic plausibility. But, as the review says, the effect is likely to be small and of short duration.

(Oddly, there have been more reported trails of infrared lasers for this sort of intervention – but that’s another story.)

So, this looks to me like a case of trying to sell a product in the absence of a robust evidence base. Good for business, perhaps, but is this good for the customers?

“Cold sores

The BioStick emits lowpower (sic) infrared light on to cold sores. A trial at Vienna Medical School found that stimulating immunity and blood flow reduced healing time for sores by up to half.

The following is a relevant clinical trial from the University of Vienna using the narrow band 690nm infrared wavelength in the treatment of herpes simplex infections. They concluded:

“Since this athermic phototherapeutic modality represents a safe, noninvasive treatment, it might be considered as an alternative to established therapeutic regimens in this indication.”

The paper referred to is Schindl and Neumann (1999). This is a small (n=50) double-blind placebo-controlled RCT. The investigators reported that, “The median recurrence-free interval in the laser-treated group was 37.5 wk (range: 2-52 wk) and in the placebo group 3 wk (range: 1-20 wk).” This result was statistically significant (p < 0.0001; Wilcoxon’s Rank Sum Test). There seems to be a lot of variability in the results for the treatment group – but there could well be something in their work.

The paper was critiqued by Rallis and Spruance (2000); they were concerned with apparent methodological flaws and, “biologic plausibility”. Schindl and Neumann (1999) appear to have been able to put up an apparantly reasonable defence of their work, but they concluded,

“We agree with Dr. Rallis that a more comprehensive assessment method should be performed in the future […]

In any case, a larger study aiming at confirming our data and investigating the mechanisms of action should certainly be performed and any collaboration with experts in the field is highly appreciated.”

The preliminary nature of this trial is clear. I can’t find any references to the larger and more comprehensive trial that the authors envisaged.

At any rate, this investigation did not use the BioStick either. It also used a slightly different wavelength. So it’s a bit rich for simplicity health to call their device ‘proven’ when the work they cite didn’t test it. Neither is it clear that the BioStick can deliver the dosage of the trial device (intensity: 80 mW per cm2, dose: 48 J per cm2).

Finally the study cited treated, “recurrent herpes simplex infections of the perioral region“. Yet, according to simplicity health, the BioStick, “has proven to be effective in the treatment of […] aphtous (sic) ulcers, and gingival inflammations.” No evidence is provided to support these claims. (Though PubMed does list a by von Ahlften on infrared laser treatment of “aphthous […] oral mucosal diseases”.)

It’s also worth noting that the company behind the Alzheimer’s LED treatment also sell the “Virulite Cold Sore Machine”. There have been a couple of publications which claim it to be effective (Dougal and Kelly, 2001; Hargate, 2006).

I’ve not been able to read either of these papers. Neither are their summaries very informative. However, a paper which looks very similar to Dougal and Kelly (2001) is freely available on-line (Dougal and Kelly, 2000). What is striking is that Virulite is claimed to be medically proven on the basis of a study which is called, “A pilot study”.

Finally, this device uses a 1072nm wavelength, rather than the 630nm wavelength used by the BioStick. Hence the Virulite papers don’t increase the evidence base for this device.

It’s clear that the commercial claims for the BioStick are constructed on an inadequate foundation of evidence.

“Acne

A trial on an infrared device, presented at the Conference of Pediatric Dermatology in Toronto, found it led to a complete or near complete recovery in 70 per cent of patients. The MediBeam handheld device was placed against the skin twice a day for six minutes.

I’ll assume that the MediBeam is the same device as the BioBeam refered to at the cited conference. Unfortunately, the trial described in the conference presentation doesn’t seem to have made it into a PubMed listed journal. There is a nice press release which the credulous Dr Chris Steele seems to have regurgitated (note the use of the expression, “enthusiastically received in medical circles.”) However, conference presentations don’t carry the weight of a journal paper – they are usually a precursor for a more formal publication.

The conference presentation was in 1992 and nothing more substantial has emerged since then.

The UK NHS National Library for Health carries a very useful summary of the evidence base for devices of this kind. Light and laser therapies for acne concludes that, “we need rigorous studies before light therapies could be recommended for acne treatment outside the research setting.”

Given the evidence that this document presents, it seems a wholly reasonable position. So, MediBeam is a device which is being sold on the basis of insubstantial evidence.

“Hair regrowth

Clinical trials on a comb that emits infrared light show that for 84 per cent of users it increases hair count by 45 per cent over eight to 16 weeks. The LaserComb Compact is approved by the FDA. Use it three times a week for ten to 15 minutes.

This is probably the least well evidenced device, to put it politely. Search as I might, I couldn’t find the clinical trial referred to anywhere. I did, however, find an excellent PubMed-listed peer-reviewed, “”consumer report” for healthcare providers and patients.”

Laser Light Therapy - Low-intensity laser light therapy has been shown to be effective in promoting wound healing60 and in improving circulation. 61, 62 For these reasons, some hair loss treatment centers are offering the use of lasers for treating alopecia in both men and women. To date, there are no known studies looking at the efficacy of these lasers for treating hair loss. The use of low-intensity laser light for treating alopecia is FDA approved for safety only, not for efficacy.29 This therapy is expensive, costing as much as $3500 for the recommended 6 months of treatment.63

Although various Web sites claim efficacy based on double-blind placebo-controlled studies of laser light treatment versus placebo laser treatment, 64, 65 such studies are not available for viewing anywhere on the Web sites. To the best of our knowledge, there are no peer-reviewed articles supporting efficacy of this type of treatment for AGA. Until reliable evidence of the effectiveness of laser light therapy for alopecia is published, this treatment remains experimental, at best.

That’ll make the laser comb a hair-loss remedy fiction then. I decided to ask a hair loss clinic who promote the Hairmax laser comb what evidence they could provide that it was effective. One of their Consultant Trichologists replied,

“Thank you for your email. We use the laser comb as a booster to the medically proven treatments that we recommend.

Please look at the website of the Hairmax laser comb to obtain the best information about the product. This laser comb is an FDA approved gadget and no review is better than an FDA approval.”

In other words they don’t consider it “medically proven”; they have no evidence to offer. I would be surprised if the FDA approval was for efficacy, rather than safety.

Again, another example where the focus is on selling a product or service, rather making sure that it works.

Given that hair loss can be a serious personal issue for some people, the excellent general caution offered by the NHS Choices website is worth noting,

“Beware of wonder cures

Hair loss can leave people feeling vulnerable. This can make them easy targets for salesmen who make false claims about expensive treatments.

It’s important to be wary of the many private clinics that advertise their celebrity-endorsed wonder cures on the back pages of newspapers.

“With hair loss, your GP should be your first stop,” says Dr David Fenton, a consultant dermatologist at St John’s Institute of Dermatology, St Thomas’ Hospital in London, who also runs a private practice.”

The Daily Mail article states, “Some forms of low-level infrared medical treatment are already available. So how can this exciting new technology help you? ”

It would be better if it looked at whether there were good reasons to suppose that any of these devices worked. From what I can, tell they haven’t been properly evaluated.

With these devices, commercial interests seem to be running roughshod over the interests of consumers. Whilst this continues to be the case, caveat emptor has to be the order of the day.

[Thanks to dvnutrix for pointing the article out to me. Apologies for not getting to it sooner.]

Edits 19th January 2009. Some comments added on reports of Sir Terry Pratchett’s use of the LED treatment for Alzheimer’s – along with a link to the Lay Scientist blog post that alerted me to it. A reference has been included to the excellent Science-Based Medicine piece posted in January 2008. A link has also been included to ABC News’ more sceptical coverage of this topic.

daedalus2usaid

I have posted a couple of blogs on what I think is the physiology behind the magic light helmet (assuming that the reports of observations that are made are factually accurate (that is the reports of effects, not explanations of effects)). The effects could be mediated through photo-dissociation of NO from cytochrome c oxidase, which would accelerate the reduction of O2, make the mitochondrial respiration chain more oxidizing (by removing those electrons onto O2) and reduce superoxide formation. In the short term this might produce the effects observed. However, if this is what it is doing, then it short-circuits the major control pathway that mitochondria have. Mitochondria have unlimited ability to produce superoxide, and the cell cannot tolerate allowing mitochondria to get out of control. Bypassing the normal first stage of regulation means that cells will invoke a later stage which is irreversible shutdown of mitochondria. If that happens to too many mitochondria, then the cell will die.

When cells are subjected to NIR light exposure, they do exhibit a reduction in mitochondrial potential (indicating the respiration chain is getting more oxidizing). They also release cytochrome c. I strongly suspect that this release of cytochrome c is a feature, a feature to restore the normal balance between mitochondrial potential and superoxide formation.

Cytochrome c release in neurons irreversibly reduces the mitochondrial capacity of those neurons because cytochrome c is only made in the cell body and is only imported into mitochondria during mitochondria biogenesis. Once it is lost, that loss is irreversible. That loss might not be apparent until it is too late. The transition from seeming to help to irreversible loss might be very abrupt. This relates to my NO research in that NO is one of the major regulators of mitochondria.

If this is what is happening (and the scheme I have outlined is consistent both with what the proponents of this device report and with what is known of mitochondria regulation), then the use of this device could cause serious and irreversible neurodegeneration even in previously healthy individuals. You might even feel better while irreversible damage is occurring.

I go into this in more detail in my blogs, with links to the literature.

My mother and both her parents died with advanced Alzheimer’s. I am sure I have inherited her phenotype. I will never use this device until the physiology behind it is understood. The risk for irreversible harm is too great.